SUMMARY Lewy body diseases, characterized by the accumulation of ?-synuclein in Lewy body structures, encompass a group of disorders with wide clinico-pathological variation, including Parkinson's disease dementia (PDD) and Dementia with Lewy Bodies (DLB). Most patients with a dominant dementia have cortical amyloid deposition, and several retrospective studies suggest that distribution and severity of Lewy body pathology impacts on clinical phenotype. Differentiation between the main synucleinopathies is based on the type and timing of clinical manifestations, with predominance of extrapyramidal motor features in PD patients and dementia in DLB cases; however, in some patients, appearance of dementia and motor impairments temporally overlap, confounding diagnosis. The lack of specific biomarkers and the co-occurrence of multiple concurring neurodegenerative syndromes in elder patients hamper determination of clinical subtypes. Epigenetic alterations, including DNA methylation and histone post-translational modifications are emerging as important contributors to neurodegenerative pathology as they have a major impact on modulating brain transcriptomes. We have previously reported alterations in DNA methylation associated with PD pathology, however, the precise epigenetic changes associated with Lewy body pathology and progression are not yet defined. Importantly, despite the impact that these alterations could potentially have on disease trajectory, they have been overlooked in the design of biomarkers and as potential outcome measures. We propose to conduct an exploratory study of DNA methylation patterns associated with DLB and PDD that will provide crucial preliminary data supporting larger studies. Importantly, we will investigate specific methylation changes in blood, searching for unique signatures that may discriminate closely related Lewy Body diseases. Development of a biomarker that aids in diagnosis of patients at early stages of neurodegeneration and that differentially diagnose cases presenting overlapping symptoms could ultimately improve disease management and therapeutic outcomes.